New provisions for the Regulation on Maximum Residue Limits

New provisions for the Regulation on Maximum Residue Limits Wissenschaftliche Prüfungsarbeit zur Erlangung des Titels Master of Drug Regulatory Affairs der Mathematisch-Naturwissenschaftlichen Fakultät der Rheinischen Friedrich-Wilhelms-Universität Bonn vorgelegt von Dr. Marcus Riehl aus Schwalmstadt Bonn 2009

Betreuer und 1. Referent: Helge Czech Zweiter Referent: Dr. Klaus Olejniczak 2

Table of Contents 1. Introduction... 6 2. Regulation (EEC) No 2377/90 the MRL Regulation... 7 2.1. Principles of the old MRL Regulation... 7 2.2. Establishment of MRLs... 7 2.2.1. Safety documentation... 8 2.2.2. Residue documentation... 9 2.2.3. MRL Assessment... 10 2.2.4. Establishment of a withdrawal period... 12 2.3. Problems and consequences of the current MRL Regulation... 13 2.4. MRL Reflection Paper on Residues in foodstuffs of animal origin... 15 2.4.1. Comments on the Reflection Paper... 15 2.4.2. Consultation of interested parties and impact assessment... 17 2.4.3. Conclusions and next steps... 18 3. EC proposal for a Regulation to replace Regulation 2377/90... 18 3.1 How to extrapolate MRLs... 22 3.1.1. Previous guidance... 22 3.1.2. Modifications of the Regulation effected by the new Proposal... 24 3.2. Alternative methods to establish an MRL... 25 4. Discussion... 29 4.1. The MRL assessment process... 29 4.2. EU and Codex MRLs... 29 4.3. Unacceptable residues in or on a food... 30 4.4. Main problem: Availability... 31 4.5. Proposals for a solution... 32 4.6. Possible further improvements... 34 5. Conclusion... 38 6. References... 39 3

List of Abbreviations ADI ADME ARD ASDI BMD bw CRL CVMP EC EEA EEC FEAP EFSA EMEA EPMAR EPP-ED EU FAO FDA FEAP FEDESA GLP IFAH- Europe ISO JECFA JMPR kg LO(A)EL LOD LOQ mg MRL MSD MUMS NO(A)EL NOEC NOEL NRL OECD OJ PBPK Acceptable Daily Intake Absorption, Distribution, Metabolism and Excretion Acute Reference Dose Acceptable Single Dose Intake Benchmark Dose Body Weight Community Reference Laboratory Committee for Veterinary Medicinal Products European Commission European Economic Area European Economic Community European fish producer association The European Food Safety Authority European Medicines Agency European Public MRL Assessment Report European People's Party - European Democrats in the European Parliament European Union Food and Agriculture Organisation Food and Drug Administration Federation of European Aquaculture Producers Fédération Européenne de la Santé Animale Good Laboratory Practice International Federation for Animal Health Europe International Organization for Standardization Joint Expert Committee on Food Additives Joint FAO/WHO Meeting on Pesticide Residues Kilogram Lowest Observed (Adverse) Effect Level Limit of Detection Limit of Quantitation Milligram Maximum Residue Limit Minimum Significant Difference Minor Use and Minor Species No Observed (Adverse) Effect Level No Observed Effect Concentration No Observed Effect Level National Reference Laboratory Organisation for Economic Co-operation and Development Official Journal Physiologically Based Pharmacokinetic Modelling 4

QRD RfD RPA SF SmPC SPC SOP UF US VICH WHO WIN Quality Review of Documents Reference Dose Reference Points for Action Safety Factor Summary of Product Characteristics Supplementary Protection Certificate Standard Operating Procedure Uncertainty Factor United States of America International Cooperation on Harmonisation of Technical Requirements for Registration of Veterinary Medicinal Products World Health Organisation Work Instruction 5

1. Introduction The main objective of the European Union (EU) legislation governing the licensing and marketing of veterinary medicines is to protect human and animal health. Veterinary medicinal products for food-producing animals can be authorised only if the foodstuffs produced will be harmless to consumers and do not contain residues of the medicine or its metabolites above the MRL. Article 6 (1) of Directive 2001/82/EC, as amended [1], states: A veterinary medicinal product may not be the subject of a marketing authorisation for the purpose of administering it to one or more food-producing species unless the pharmacologically active substances which it contains appear in Annexes I, II, or III to Regulation (EEC) No 2377/90. Regulation (EEC) No 2377/90 [2] as amended laying down a Community procedure to evaluate the safety of residues of pharmacologically active substances. The Annexes are regularly updated by Commission and Council Regulations which are published by the Commission on the DG Enterprise website [3]. According to this Regulation residues of veterinary medicinal products are defined as all pharmacologically active substances, whether active principles, excipients or degradation products, and their metabolites. Maximum residue limits (MRLs) have to be established for active substances and if applicable also for excipients (EudraLex - Volume 8) [4]. An MRL is defined as the maximum concentration of residues resulting from the use of a veterinary medicinal product (expressed in mg/kg or µg/kg on a fresh weight basis) which may be accepted by the Community to be legally permitted or recognized as acceptable in or on a food. The Committee for Veterinary Medicinal Products (CVMP) also publishes a list of substances [5] not falling within the scope of Council Regulation (EEC) No 2377/90 [2], as amended. These substances are classified as normal components of human food, biologically inert when orally taken, or non chemicals.the MRL Regulation does not apply to active substances of biological origin intended to produce or to diagnose active or passive immunity used in immunological veterinary medicinal products. The time between the last medication of a food producing animal and the time when the level of residues in the tissues or products (muscle, liver, kidney, milk, eggs, honey or other edible products) is lower, or equal to the MRL determines the withdrawal period/withholding period. Until this time has elapsed, the animal or its products must not, by law, be used for human consumption. Withdrawal periods exist so that MRLs are not exceeded and to ensure consumer safety. As a result, although residues above the MRL should not occur, even if they do, they generally present no risk to the consumer because of the very large safety margins used in setting the MRL. The primary purpose of establishing MRLs is to ensure the protection of the consumer against possible harmful effects resulting from exposure to residues. Thus MRLs are to be established in accordance with general principles of a safety assessment. The current regulation contributed to protect human and animal health and welfare but it also had a strong impact on the availability of veterinary medicinal products, especially for food producing animals. To overcome this problem, the European Commission suggested to review the existing regulation. The aim of this thesis is to describe the current regulation and the problems associated with it, as well as the new proposal [6], which will replace the current regulation. It is discussed, to which extend the new proposal provides changes to overcome the existing problems and which further approaches could help to improve the current situation. 6

2. Regulation (EEC) No 2377/90 the MRL Regulation 2.1. Principles of the old MRL Regulation On 26 June 1990 the Council adopted Regulation (EEC) No 2377/90 [2] laying down a Community procedure for the establishment of maximum residue limits of veterinary medicinal products in foodstuffs of animal origin. Consequently, pharmacologically active substances could not be used without positive evaluation in food producing animals. After a transition period from 1 January 2000 onwards veterinary medicinal products without a MRL have been withdrawn from the EU market. The primary goal of this regulation is to ensure food safety and hence the protection of human health. Another important aspect is to allow the free movement of food of animal origin within the entire EC - market. The central aspect of Regulation (EEC) No 2377/90 [2], as amended is the establishment of maximum residue limits (MRLs) for veterinary medicinal products in foodstuffs of animal origin if considered necessary. Regulation (EEC) No 2377/90 [2], as amended is assessing the safety of residues by combining risk assessment, risk management and risk communication [7]. Risk assessment is a first step in a risk management process, starting with the identification of a hazard which may cause adverse effects towards animal health followed by the determination of the probability of occurrence. This hazard then has to be characterised, analysing it qualitatively and/or quantitatively. At this stage the acceptable daily intake (ADI) is established. Using a marker residue an estimation of the consumer intake can be performed to get a view on the exposure assessment. The last step in the risk assessment is the risk characterisation where it is decided, whether an MRL needs to be established. Therefore the risk has to be estimated qualitatively and/or quantitatively to which the consumer may be exposed to residues resulting adverse effects to human health. Risk management is a tool consisting of several steps to reduce or avoid a risk by using strategies to control the risk (e.g. the establishment of withdrawal periods following the assessment of new pharmacologically active substance in the MRL procedure, which normally leads to the inclusion into Annex I IV of Council Regulation (EEC) No 2377/90 [2], as amended). Risk communication is the process in which all information relating the risk are communicated to all parties involved and interested in the process (e.g. EMEA Summary Reports). 2.2. Establishment of MRLs The main principle for the MRL assessment is summarized in the Guideline "Note for guidance on the risk analysis approach for residues of veterinary medicinal products in food of animal origin" [7]. Information and particulars to be included in an application for the establishment of a maximum residue limit for a pharmacologically active substance used in veterinary medicinal products are listed in ANNEX V of Council Regulation (EEC) No 2377/90 [2], as amended, in the EudraLex - Volume 8 [4]. and on the homepage of the 7

European Medicines Agency (EMEA) [8]. Also the EMEA Standard Operating Procedures (SOP) and Work Instructions (WIN) should be followed. The application shall also conform with the principles laid down in Directive 81/852/EEC [9] and the articles 52 and 53 of Regulation (EEC) No 2309/93 [10]. Studies should be performed according to the Guidelines of the CVMP and Good Laboratory Practice (GLP) [11]. Also the CVMP Note for Guidance on the Establishment of Maximum Residue Limits for Minor Animal Species [12] should be taken into consideration. About 3-4 months before the submission of an application for the establishment of MRLs, the applicant has to contact the EMEA. After the CVMP meeting at which the letter of intent is considered, the applicant will be notified about the procedural details. The time line for an MRL application is defined in article 6 of Council Regulation (EEC) No 2377/90 [2], as amended. The MRL application should be submitted at least six months before the submission of the dossier (Article 12 of Directive 2001/82/EC, as amended). The CVMP has to give its opinion within 120 days after receiving the application (120-day time limit without clock-stop for questions; the time frame for answers is normally 6 months). To apply for an MRL the applicant has to supply a dossier consisting of a safety and a residues documentation to the CVMP which prepares the assessment. All data which have to be provided and studies/testings which have to be performed are described in the documents mentioned above. Therefore only the most important points are summarized in the following. 2.2.1. Safety documentation The Safety Documentation (Part III A of the dossier) contains all the pharmacology and toxicology studies carried out with the medicine in laboratory animals. These studies examine what happens to the substance in the body and assess how much can be given safely, without inducing any unwanted adverse effects. From a series of required toxicological studies a No Observed Effect Level (NOEL) is established (expressed in mg/kg), below which administration of a certain dose of a product has absolutely no effect on the animal, either clinically, toxicologically or biochemically. In certain cases the NOEL is also expressed as no observed (adverse) effect level (NO(A)EL) or, the lowest observed (adverse) effect level (LO(A)EL). The NOEL is divided by a safety factor to give extra safety for human consumers. It is therefore prudent to adjust for possible differences by assuming that humans are more sensitive than the most sensitive test animal. Traditionally a safety factor of 100 has been used, to account for the differences between test animals and humans (factor of 10) and possible differences in sensitivity between humans (another factor of 10). The World Health Organisation (WHO) recommends a safety factor of between 100 and 1000 (usually depending on the type of effect). The NOEL is used to determine the Acceptable Daily Intake (ADI) of the product which may be consumed by a human being without causing any adverse effect. More specifically, the ADI is defined as the amount of a specific substance in food or drinking water that can be ingested per day over a lifetime without a measurable pharmacological, toxicological or microbiological effect (expressed in mg/kg body weight/day or, referring to a average human bodyweight of 60 kg). 8

ADI (mg/kg bw) = NOEL (mg/kg bw/day) Safety Factor (SF) This concept was first introduced in 1957 by the Council of Europe and also later by the Joint Expert Committee on Food Additives (JECFA). The ADI may be set on the basis of toxicological, pharmacological or microbiological data, whichever is the lowest [7]. The estimation of the consumer intake also takes into account the residue concentration in the food commodities derived from the pattern of residue depletion of the substance in the target animal. Where appropriate residues from the pesticide use of a substance are also taken into account. For antimicrobial substances there is an additional safety assessment to determine a microbiological ADI, based on the effect of the substance on the normal gut bacterial flora found in humans (methodologies for establishing a microbiological ADI are described in the VICH guideline 36 (CVMP/VICH/467/03-FINAL-corr) [13]). For the calculation of microbiological ADIs based on in vitro data, safety factors are already included in the formula. For in vivo models the safety factors is calculated in the same way as for the toxicological ADI. The substantial safety margin used to calculate the ADI is considered necessary to cover the substantial uncertainties in the models used and their relevance to a diverse population of consumers. According to EudraLex - Volume 8 [4], the ADI concept is not applicable to substances for which it is not possible to determine a NOEL because they demonstrate non-threshold effects (such as genotoxicity and delayed neurotoxicity). In such cases, an alternative approach to safety evaluation may be applied on a case by case basis, having regard to all the data available. In the safety documentation, also official assessments of CVMP, JECFA and JMPR (Joint Meeting of the FAO Panel of Experts on Pesticide Residues in Food and the Environment and the WHO Expert Group on Pesticide Residues), should be included. The safety documentation is completed by an expert report. 2.2.2. Residue documentation The Residues Documentation (Part III B of the dossier) contains all the data concerning the formation, nature, behaviour and disappearance of residues after a medicine has been given to a food producing animal which are necessary to determine the withdrawal period. The additional data necessary to determine MRLs are based on the results contained in the safety documentation. Residues of veterinary medicinal products (in accordance with Article 1 (1) (a) of Council Regulation (EEC) No 2377/90 [2], as amended), are defined as all pharmacologically active substances, whether active principles, excipients or degradation products, and their metabolites which may remain in foodstuffs obtained from animals to which the veterinary medicinal product has been administered. A tool to assess the MRL are marker residues which are identified on the basis of pharmacokinetic and depletion studies. Marker residues are substances or metabolites which decrease in a known relationship to the concentration of total residues in tissues, eggs, milk or other animal tissues. The marker residue is not necessarily a residue of toxicological or microbiological concern and has to be mentioned in the residue documentation. When 9

establishing a MRL, consideration is also given to residues that occur in food of plant origin and/or come from the environment. The residue levels that can remain in tissues are called the MRLs. Where necessary, MRLs should be established for all food commodities (muscle, fat (fat and skin where appropriate), liver and kidney, meat of fin fish (muscle and skin in natural proportions), milk, eggs and honey) from food producing animals. The maximum concentration of residue following administration of a veterinary medicine are determined in such a way that the sum of the residues (which may cause a health risk) in a defined daily consumption portion (Standard Food Basket) of the food of animal origin does not exceed the ADI. The calculation assumes an average daily food intake of 500 g meat and offal or 300 g fish, 1,5 l milk, 100 g eggs and 20 g honey. For the documentation also data from literature and if possible data which refer to similar substances should be provided. The applicant and the expert (writing the expert report for the Residue documentation) propose MRLs for all relevant pairs of marker residue and edible tissue taking into account the safety data and the proposed ADI. The proposed MRLs must meet the requirements laid down in Council Regulation (EEC) No 2377/90 [2], as amended. Applicants have to submit also the validated analytical method for all the tissues for which MRLs have been set (as required in Annex V to Council Regulation (EEC) No 2377/90 [2], as amended). This method should be validated across a range which at least includes one-half and twice the MRL and it also should determine the marker residue on which the MRLs are based. Commission Decision 2002/657/EC, as amended [14] establishes criteria and procedures for the validation of analytical methods to ensure the quality and comparability of analytical results generated by official laboratories. 2.2.3. MRL Assessment MRLs are set by the European Commission (EC) or the Codex Alimentarius Commission. The Codex Alimentarius (Codex) was established in 1963 by FAO (Food and Agriculture Organisation) and WHO (World Health Organisation). The Codex aims to protect the health of consumers, ensure fair trade practices in the food trade, and promote co-ordination of all food standards work undertaken by international governmental and non-governmental organisations [15]. It aims to enable the harmonisation of food standards and is used by the WTO (World Trade Organization) as the benchmark against which national food safety is measured. The Codex MRLs are set as standards for food and they are not statutory for the authorization of pharmacologically active substances in veterinary medicinal products in the EU. Since September 2008 all statutory MRLs regarding foods treated with pesticides are listed in EC Regulation 396/2005(EC) [16]. Therefore, the assessment for an MRL regarding active substances in veterinary medicinal products in the EU is set on a case-by-case basis by the EC after adoption by the Standing Committee, following an opinion of the CVMP. 0.300 kg of muscle, 0.100 kg of liver, 0.050 kg of kidney and 0.050 kg of fat (for pigs, fat and skin in natural proportions) and for poultry 0.300 kg of muscle, 0.100 kg of liver, 0.010 kg of kidney and 0.090 kg of fat and skin in natural proportions 10

The assessment of a new pharmacologically active substance in the MRL procedure normally leads to the inclusion into Annex I IV of Council Regulation (EEC) No 2377/90 [2], as amended: Annex I: List of pharmacologically active substances for which maximum residue levels have been fixed (Substances with final MRLs) The data in the dossier are considered adequate to establish a final MRL. Annex II: List of substances not subject to maximum residue levels (Substances for which MRLs are not necessary) The data in the dossier demonstrate that there is no risk to the consumer and MRLs are not needed. The application of some substances is subject to restrictions (e.g. only external use or restricted for described animal species). Annex III: List of pharmacologically active substances used in veterinary medicinal products for which maximum residue levels have been fixed (Substances with provisional MRLs) This is for medicines for which MRLs can be established but some clarification of further studies are required before final MRLs can be set. The provisional MRLs are valid for a maximum of 5 years. Annex IV: Lists of pharmacologically active substances for which no maximum levels can be fixed (Substances that cannot have an MRL) Residues of the medicine pose an unacceptable risk to the consumer or there is insufficient information to allow a full assessment. The products in Annex IV are prohibited for use in food producing animals in the European Union. If a substance can not be included in Annex I-IV (e.g. insufficient data were presented for evaluation to the CVMD) this also means that the substance may not be used for treatment of food producing animals. The applicant has the right to appeal against the CVMD opinion within 15 days after receipt (in accordance with Article 7 of Council Regulation (EEC) No 2377/90 [2], as amended). Otherwise, the opinion becomes final and will be submitted together with the Summary Report and analytical method, where appropriate, to the European Commission within 30 days after adoption by the CVMP. The Commission will then prepare a draft Commission Regulation to amend Annex I, II, III or IV as appropriate and submit it to the Standing Committee on Veterinary Medicinal Products for adoption in accordance with the procedure laid down in Article 8 of Council Regulation (EEC) No 2377/90 [2], as amended. The annexes are regularly updated by Commission Regulations which are then published in the Official Journal (OJ) of the European Communities and on the European Commission website [17]. Additionally, the European Public MRL Assessment Report (EPMAR, formerly called Summary Report) is published containing more detailed information. Since 1 January 1992 the MRL has to be published before a veterinary medicinal product for food producing animals can be registered in the EU. Older pharmacological active substances had to be assessed until 1 January 2000. Due to article 14 of Council Regulation (EEC) No 2377/90 [2], as amended, since 1 January 2000 the administration of veterinary medicinal products containing pharmacological active substances for which no MRL was accomplished to food producing animals is forbidden in the EU. The CVMP issued in 1995 a list of substances [18] not falling within the scope of Council Regulation (EEC) No 2377/90 [2], as amended, because some substances were normal components of human food, biologically inert when orally taken, or not classified as 11

chemicals. This list is regularly updated and includes also substances for which no formal MRL application had been made and substances which were originally the subject of an intention to submit or even an actual application but subsequently classed as not within the scope of Council Regulation (EEC) No 2377/90 [2], as amended. Once the MRL is published, it has to be inserted into the dossier Part IIIB (according to Volume 6B - Notice to applicants - Presentation and content of the dossier). The MRL is not protected and can be referred to by any pharmaceutical company for the application of a marketing authorisation of a veterinary medicinal product. 2.2.4. Establishment of a withdrawal period The determination of withdrawal periods is a complex affair, but considered essential to ensure the safety of the consumer. Once MRLs have been published (EMEA Summary Reports) sequentially in the Official Journal of the EU (arbitrative) and on the EMEA homepage [17], it is then necessary in the context of granting a marketing authorisation (in accordance with Directive 2001/82/EC as amended and Regulation 726/2004/EC) to determine a withdrawal period for veterinary medicines; this ensures that residues from the product concerned will not exceed the MRLs. The time between the last medication of a food producing animal and the time when the level of residues in the tissues or products is lower, or equal to the MRL determines the withdrawal period required before animals can be sent for slaughter and used for human consumption. The withdrawal periods for animal slaughter as well as for the production of milk, eggs and honey for human consumption are determined from the results of suitable residue depletion studies using the formulation intended for marketing. The withdrawal period depends on the active substance, composition of the excipients, pharmaceutical form, route and duration of application. It is product specific and species specific. Article 12 of Directive 2001/82/EC, as amended, states: At least six months shall elapse between a valid application for the establishment of maximum residue limits and an application for a marketing authorisation. Therefore a dossier has to be submitted to the responsible authorities consisting of part I - IV (in accordance with Volume 6 - Notice to Applicants: Veterinary Medicinal Products). The two parts of the dossier on safety and residues which have been used for the MRL assessment (in accordance with Council Regulation (EEC) No 2377/90 as amended and Notice to applicants Vol. 8) have to be completely included as Part III A (Safety) and Part III B (Residues), (except points (i), (ii) or (iii) of Article 13(1)(a) of Directive 2001/82/EC have been submitted). The applicant and the expert (writing the expert report for the Residue documentation) propose withdrawal periods for all food producing animal species taking into account the proposed MRL based on the following guidelines which are available on the EMEA website [19]: Notes for Guidance regarding withdrawal periods for animal tissues (EMEA/CVMP/036/95) [20] and milk (EMEA/CVMP/473/98) [21] were published by the CVMP in order to ensure a uniform approach to establish withdrawal periods throughout the EU (EEC). Corresponding computer programs for the calculation of the withdrawal periods in accordance with these guidelines are available on the EMEA website in the same section. 12

The withdrawal period is assessed during the registration process of the veterinary medicinal product. Depending on the procedure chosen by the applicant to obtain a marketing authorisation for the veterinary medicinal product, proposed withdrawal periods will either be approved by a Member State (national, decentralized or mutual recognition procedure), or by the CVMP (central procedure). Once the withdrawal period is assessed, the SmPC, primary and secondary packaging materials, package leaflet (according to the QRD templates) [22] and also the dossier (Part IIIB and expert report) have to be updated, if necessary. A change in the composition of the product may cause a different withdrawal period. For equidae there is a special situation. A list of substances essential for the treatment of equidae is published in the Council Regulation No 1950/2006 [23]. Veterinary medicinal products without a MRL for equidae, or used "off-label", or used under the Cascade provision and which are not on "the essential" or the "positive list" for equidae referred to in Article 10(3) and 11 of Directive 2001/82/EC and which are not administered intra-muscularly or subcutaneously are subject to a withdrawal period of at least six months. 2.3. Problems and consequences of the current MRL Regulation The Community legislation on residues of pharmacologically active substances (Council Regulation (EEC) No 2377/90 [2], as amended) is a complex system which is distributed over several pieces of procedures and legislative tools. On one hand the implementation of the legislation has increased the consumer protection, animal health and animal welfare but on the other hand the current inflexibility is resulting in numerous difficulties: Reduced number of medicines available for food-producing animals The requirement of establishing MRLs is associated with high costs for collecting the required scientific data and assembling the documentation. These data include information and studies on the pharmacology, toxicology, pharmacokinetics and depletion of residues of the pharmacologically active substances (and their metabolites) from the target tissues for all animal species applied. Also the validated methods for the detection and quantification of the residues have to be provided. These additional costs result in a reduced number of veterinary medicinal products available in Europe for the treatment of food-producing animals to an extent that creates adverse problems in the medical care for public and animal health and welfare. Already in 1995 the Federation of European Aquaculture Producers (FEAP), produced a list of 62 therapeutic agents (excluding vaccines) which were used in fish farming in the EU (FEAP 1995): of those 43 were absolutely needed and only 27 were likely to be authorised to remain on the market after the completion of the MRL evaluation, i.e. by the end of 1999 [24]. Council Regulation (EC) 1950/2006 [23] provides a list of substances essential for the treatment of equidae, which are also affected by the decreased number of medicinal products available for food producing animals. The withdrawal period for each of the listed substances for equidae intended for slaughter for human consumption shall be at least six months. 13

Strict limitations on the flexibility allowed to veterinary surgeons in using or prescribing veterinary medicines Another effect of the reduced number of veterinary medicinal products available is that veterinary surgeons increasingly have to adopt the Cascade provision, which means that the product is being used under their personal responsibility. Against the background of this provision veterinary surgeons are in exceptional cases allowed to prescribe medicines off-label within very strict limitations if it is necessary to avoid unacceptable suffering and where no suitable product exists for the treatment of an animal under his/her direct personal responsibility. The veterinary surgeon also has to set an appropriate withdrawal period for the slaughter of treated animals or for the production of milk, eggs or honey. But even using the Cascade provision according to Article 10 and 11 of Directive 2001/82/EC [1], some therapeutic gaps remain. Problems related to the control of residues in foods of animal origin In the EU, the veterinary pharmaceutical companies are responsible for the production of veterinary medicinal products in accordance with the corresponding marketing authorisations. The Member States are responsible for the control of residues resulting from the use of these products. In 2004 the Regulation (EC) No 882/2004 [25], as amended was introduced to ensure the verification of compliance with feed and food law, animal health and animal welfare rules. This regulation has improved the residue control in the Community and contributed significantly to the harmonisation of control, but it also was criticised e.g. because of its inflexibility (it was impossible to react to recent residue findings and delay in obtaining and evaluating of results and sampling requirements). With the current legislation, international standards supported by the EU cannot be included in Community legislation without a new scientific assessment by the EMEA. Classification of all pharmacologically active substances into a specific annex Article 6 of Directive 2001/82/EC [1] requires the inclusion of a pharmacologically active substance in annexes I, II or III of Regulation 2377/90 as a precondition for obtaining a marketing authorisation for veterinary medicinal products for food producing animals. Limitations in the extrapolation of MRLs from one species to another After implementation of Council Regulation (EEC) No. 2377/90, the CVMP already realized, that there was a need for a more pragmatic approach for the extrapolation of MRLs from one species to another, especially those classified as minor species. Therefore several CVMP proposals were published (e.g. EMEA/CVMP/153a/97 [12], EMEA/CVMP/153b/97 [26], EMEA/CVMP/187/00-FINAL [7], EMEA/CVMP/069/02 [27]), resulting only in a slight improvement regarding the availability of veterinary medicinal products. Insufficient procedures for the establishment of a short-term risk assessment for certain residues detected in imported food Residues of substances not authorised in the EU should not be present in imports to the EU. In food imported from third countries, residues from substances not authorised in the EU have been detected from different Member States at differing concentrations. The Member States which didn t detect the residues or found them to be below the MRL accepted this food for import, the others rejected it, which leads to a dis-harmonisation within the EU. The Member States also do not have reference points of action (RPA) in particular for substances detected in food from third countries. 14

The current legislation is difficult to understand The current legislation is a complex system which is partly circuitous and mistakable formulated. Additional reasons for criticism are the complexity, data requirements for the MRL documentation and the additional scientific assessment for Codex MRLs causing high costs and problems in comprehensibility. 2.4. MRL Reflection Paper on Residues in foodstuffs of animal origin In December 2003 a Reflection Paper [28] was published by the Commission analysing the difficulties (mainly decreased availability of medicines and problems related to international trade) of the current Community legislation concerning residues of pharmacologically active substances in veterinary medicinal products for food producing animals. The main issues of the Reflection Paper on which comments and proposals are solicited are the following: Structures for the appropriate differentiation of risk assessment and risk management for the evaluation and control of residues in food of animal origin Procedures for extrapolation of maximum residue limits Procedures for provision of reference points for control purposes Procedures for precautionary measures for substances in imported foodstuffs Procedures for short-term risk assessments in crisis situations Procedures for the evaluation of Third Countries residue control measures Procedures for the nomination of Community reference laboratories Procedures for the establishment of plans for monitoring and targeted controls Financing of measures of interest to the Community related to food safety Residue control specific enforcement measures 2.4.1. Comments on the Reflection Paper Comments on the Reflection Paper from more than 40 sources (e.g. EMEA, Member States, countries outside the EU, animal health industry, organisations of the European food industry, individual persons) were received and analyzed [29, 30]. The majority of comments were related to the following 7 topics: 1. General comments More flexibility and harmonization (e.g. for risk analysis and residues control) Avoidance of new studies resulting in higher costs and less available medicines Reorganisation of the annexes to Regulation (EEC) No 2377/90 as amended 15

Clear scopes and definitions 2. Residue monitoring and enforcement Harmonised sampling procedures, reporting and action in relation to non-compliance Reorganization of national monitoring plans to save resources Sample selection according to risk analysis principles and occurrence of prohibited substances Establishment of a feedback mechanism between the residue evaluation procedure according to Regulation (EEC) No 2377/90, as amended, and the monitoring Spread of the monitoring activities (Exposure, Community targeted, national/ad hoc targeted on suspicion) Review of substances in Annex I of Directive 96/23/EC and deletion of contaminants More self-regulatory approaches concerning the product responsibility 3. Imports of food from third countries Regularly up-dated evaluation of third countries according to authorisation schemes, control of production and use, identification of prohibited substances and monitoring plans Harmonised sampling plans and sampling procedures following risk assessment principles as within the Community (same methods and detection limits) 4. Minimum requirement performance limits and zero tolerance Review and modification of the legislation on prohibited substances (e.g. zero tolerance approach for prohibited substances as in Annex IV of Regulation (EEC) No 2377/90 as amended, but also regarding all substances prohibited under Directive 96/22/EC [31]) Establishment of harmonised action limits for the evaluation of food that contained residues of these substances (based on laboratory performance capabilities and a basic toxicological evaluation) Setting of default limits (temporary in case of urgent need) Harmonised reporting and enforcement measures in case of unauthorised use 5. Structure and performance of the Community reference and control laboratories Review of the CRL (Community Reference Laboratory) and NRL (National Reference Laboratory) network (e.g. workload, competence, development and validation of methods, adequate financing to ensure independence) 6. Risk analysis Review and differentiation/separation of risk assessment and risk management (not entirely possible in all cases) Risk assessment should also focus more on estimates of real consumer exposure to residues (in case of missing data, default levels should be introduced) 16

Proposals for risk management options, including other legitimate factors, could form part of the risk assessment Harmonised risk analysis procedures for all types of residues (for veterinary medicines, pesticides and feed additives as well as contaminants) Risk/benefit analysis of substances used in veterinary medicinal products Review and Re-evaluation of existing MRLs Adoption of agreed Codex Alimentarius MRLs as EU standards Temporary risk assessments (e.g. in crisis situations) Find responsible body for risk evaluation of (and set limits for) residues of nonauthorised substances (e.g. EMEA or EFSA) 7. Availability of veterinary medicinal products in the EU The implementation of Council Regulation (EEC) No 2377/90, as amended on MRLs has contributed to reduce the number of medicines available for food-producing animals (lack of authorised veterinary medicinal products for fresh-water fish and bees) Review of data requirements for the establishment of MRLs (e.g. validation of the residue analytical method) Introduction for extrapolation of MRLs to additional species (based on scientific principles) Data protection for MRL documentations 2.4.2. Consultation of interested parties and impact assessment After publication of the Reflection Paper the Member States organized meetings in 2004 and 2005 where ideas for legislative amendments were discussed. These proposals had been identified by six expert Working Groups. The European Commission also requested the stakeholders to complete a specific questionnaire which was then evaluated by the Expert Working Groups. The results were summarized in an impact assessment [32] with three main policy options: Option 1 - Maintain the current legal framework. Nothing would change so the problems would be unresolved (e.g. availability of veterinary medicinal products for food producing animals). Option 2 - Review the existing regulation. The shortcomings of Regulation (EEC) No 2377/90 [2], as amended, will be corrected by incorporating specific legal provisions and amending existing rules, while leaving the overall system of setting MRLs based on scientific assessment intact. Option 3 - Replace the existing legislation by guidelines. This would on the one hand simplify the legislative requirements resulting in more flexibility for both competent authorities and to the industry, on the other hand it would result in a deregulation (e.g. different levels of food safety). It was concluded that this option does not meet the objectives and purposes defined by the Commission. 17

2.4.3. Conclusions and next steps Based on the comments the Commission will analyse the different topics and propose amendments to the current legislation. This should improve consumer protection, animal health, welfare and trade requirements concerning residues of pharmacologically active substance used in veterinary medicinal products in food producing animals. Also it is aimed to harmonize the new legislation with the Food Law [33] and approaches regarding residues from use of feed additives, pesticides and biocides, where appropriate. This would in conclusion result in a more consistent approach for the risk analysis and control of residues of such substances, which may appear in food produced in or imported into the European Union. 3. EC proposal for a Regulation to replace Regulation 2377/90 The current Regulation (EEC) No 2377/90 [2], as amended, guarantees a high level of public health protection but it contributed to several problems. On 17 April 2007 the European Commission adopted the Proposal for a Regulation of the European Parliament and of the Council laying down Community procedures for the establishment of residue limits of pharmacologically active substances in foodstuffs of animal origin, and repealing Regulation (EEC) No 2377/90 [6] based on Article 152 (4) (b) of the EC Treaty (triggering the start of the co-decision procedure with the European Parliament and the Council of the EU). The proposal is reflecting the consultation on possible changes launched in 2004 by the Commission. The current regulation will be modified, but the principle of the MRL assessment will be retained. The new proposal of the Commission has four main objectives: 1. To improve the availability of veterinary medicinal products for food producing animals in order to ensure animal health and welfare and avoid illegal use of substances 2. To simplify the existing legislation by enhancing readability of the provisions on established MRLs for the end-users (i.e. animal health professionals, control competent authorities in Member States and third countries) 3. To provide clear references for the control of residues of pharmacologically active substances in foodstuffs to improve consumer health protection and the functioning of the 'single market' 4. To clarify the Community procedures establishing MRLs by ensuring consistency with international standards The proposal for the new Regulation aims to review and simplify existing provisions related to the establishment of MRLs for residues of pharmacologically active substances in veterinary medicinal products legally accepted in foodstuffs of animal origin. There will be a separation for the procedure to set MRLs from the procedure to apply for a marketing authorization. Additionally it aims to continue to limit consumer exposure to residues of pharmacologically active substances in foodstuffs of animal origin thus to improve the level of animal welfare, animal health and consequently ensure a high level of consumer health protection. The 18

regulation should improve the availability of veterinary medicinal products in the Community and reduce the off-label use. These objectives can be reached by introducing the following changes to the current Regulation: Extrapolation of MRLs to other species Because of the high costs of increasing regulatory requirements for the establishment of MRLs for use in food-producing species has led to a reduced number of authorised medicines available for minor species (e.g. goats and bees) or therapeutic classes in the EU. The new Regulation proposes to establish principles to extrapolate data on metabolism and residue distribution of pharmacologically active substances (MRLs) which have been set for a specific species to other species and/or foodstuffs, where an authorised product is not available. A risk assessment can be performed by independent experts. So no new data have to be provided and additional costs are avoided. The principles for extrapolation will be a compulsory part of the overall scientific assessment. Adapt Codex MRLs without a further risk assessment MRLs are set by the European Commission or the Codex Alimentarius Commission. The EU is a member of the Codex and thus involved in the MRL assessment of the Codex Alimentarius Commission. Currently for Codex MRLs a further risk assessment is conducted before they are accepted by the EU. The new Community legislation introduces an obligation to adapt Codex MRLs without further risk assessment, assumed that the scientific basis is adequate to avoid any risks for animal and human health. So no separate scientific assessment of active substances which have been assessed by the Codex Alimentarius Commission have to be performed. This results in reduced costs, an accelerated time period to obtain a marketing authorization and thus in more medicinal products available for food producing animals. Create a legal framework to set MRLs for substances not authorized in the EU Based on Council Regulation (EEC) No 2377/90 [2], as amended, veterinary medicinal products for food-producing animals without a MRL have been withdrawn from the EU market. The problem is imported food containing substances not authorised for use in the EU. Some of these substances are banned, but others were never assessed. Until now for these residues the principle of zero tolerance was applied which was complicated by the increasing analytical possibilities to detect residues at ever lower levels. Some EU countries started to set their own limits resulting in a disharmonisation within the Community. In 2002 and 2005 the Commission adopted Commission Decision 2002/657/EC and Commission Directive 2005/34/EC [14, 34], which established minimum required performance levels (MRPLs) for banned substances found in exports from third countries, based on the analytical levels which the control laboratories in all Member States would be able to detect. The new proposal is intended to help to create a legal framework to establish MRLs for pharmacologically active substances not intended for use in veterinary medicinal products in the EU. In the case MRLs have not been set, RPAs should be established and communicated to the European Food Safety Authority (EFSA). For the suitability of these RPAs a risk assessment will be performed by EFSA. This will improve the international trade of foodstuffs and mainly ensure a high level of consumer health protection. 19

MRL assessment for substances used as biocides in animal husbandry The legal framework is presented in the Biocides Directive [35]. Residues of Biocides (such as disinfectants) used for animal treatment may also occur in foodstuffs. Therefore, the Commission suggested to set MRLs for pharmacologically active substances used in Biocides. The assessment procedure should be comparable to the assessment procedure for the establishment of MRLs for pharmacologically active substances used in veterinary medicinal products. Also the unsolved problem of the fees for the assessment will be addressed in the new legislation, because until now biocides fall under the European Food Standards Agency's responsibilities. Simplification and better regulation of the legislation The current legislation is a complex system which is distributed over several pieces of procedures and legislative tools. The review of the MRL Regulation proposes to reorganize the complete legislation and to integrate the MRLs (currently arranged in 4 annexes) in a single Regulation and perhaps to arrange them in an alphabetic order. The readability and comprehensibility of the regulation should be improved. This will also enhance the compliance, especially for third countries exporting foodstuffs of animal origin in the Community. Other topics To ensure human and animal health and welfare, the Commission may grant urgent authorizations. If required, the Parliament has to establish provisional MRLs (based on Council Regulation (EEC) No 2377/90 [2], as amended) for a period not exceeding five years. It is proposed to achieve more flexibility regarding the availability of veterinary medicinal products for horses. If the medicine does not have a MRL for equidae, which are not included in Annex IV or in Article 13(2) of Regulation (EEC) No 2377/90 [2], as amended, or which are: - used "off-label", as defined in Article 1(16) of Directive 2001/82/EC - used under the cascade provision - not administered intra-muscularly or subcutaneously - not on "the essential" or the "positive list" for equidae referred to in Article 10(3) of Directive 2001/82/EC shall have a nominal withdrawal period of six months to ensure that consumers are not exposed to unacceptable residues. Some member states stressed the need to request an opinion from the Agency (EMEA) under certain conditions on MRLs for substances not intended to be used in veterinary medicinal products to be placed on the market in the Community (such as biocidal products). Another problem are substances, which are used for different purposes (such as pesticides and veterinary medicinal products) because they may have different MRLs, published in different pieces of the legislation. Also discussed amendments were a regularly review for RPAs because of the developing analytical methodology which could lead to an endless chase towards zero residues, or the amendment for an additional safety factor when extrapolating MRLs between species. 20